The present invention relates to anti-neoplastic and anti-psoriasis pharmaceutical compositions and methods of treatment and to insecticidal compositions and methods of controlling the growth of insects.
In recent years a great deal of attention has been focused on the polyamines, e.g., spermidine, norspermidine, homospermidine, 1,4-diaminobutane (putrescine), and spermine. These studies have been directed largely at the biological properties of the polyamines probably because of the role they play in proliferative processes. It was shown early on that the polyamine levels in dividing cells, e.g., cancer cells, are much higher than in resting cells. See Janne et al, A. Biochim. Biophys. Acta. 473, 241 (1978); Fillingame et al, Proc. Natl. Acad. Sci. U.S.A. 72: 4042 (1975); Metcalf et al, J. Am. Chem. Soc. 100:2551 (1978); Flink et al, Nature (London) 253:62 (1975); and Pegg et al, Polyamine Metabolism and Function, Am. J. Cell. Physiol. 243:212-221 (1982).
Several lines of evidence indicate that polyamines, particularly spermidine, are required for cell proliferation: (i) they are found in greater amounts in growing than in non-growing tissues; (ii) prokaryotic and eukaryotic mutants deficient in polyamine biosynthesis are auxotrophic for polyamines; and (iii) inhibitors specific for polyamine biosynthesis also inhibit cell growth. Despite this evidence, the precise biological role of polyamines in cell proliferation is uncertain. It has been suggested that polyamines, by virtue of their charged nature under physiological conditions and their conformational flexibility, might serve to stabilize macromolecules such as nucleic acids by anion neutralization. See Dkystra et al, Science, 149:48 (1965); Russell et al, Polyamines as Biochemical Markers of Normal and Malignant Growth (Raven, New York, 1978); Hirschfield et al, J. Bacteriol., 101:725 (1970); Morris et al, ibid, p. 731; Whitney et al, ibid, 134:214 (1978); Hafner et al, J. Biol. Chem., 254:12419 (1979); Cohn et al, J. Bacteriol. 134:208 (1978); Pohjatipelto et al, Nature (London), 293:475 (1981); Mamont et al, Biochem. Biophys. Res. Commun. 81:58 (1978); Bloomfield et al, Polyamines in Biology and Medicine (D. R. Morris and L. J. Morton, Eds.xe2x80x94Dekker, New York, 1981) pp. 183-205; Gosule et al, Nature, 259:333 (1976); Gabbay et al, Ann. N.Y. Acad. Sci., 171:810 (1970); Suwalsky et al, J. Mol. Biol., 42:363 (1969) and Liquori et al, J. Mol. Biol., 24:113 (1968).
However, regardless of the reason for increased polyamine levels the phenomenon can be and has been exploited in chemotherapy. See Sjoerdsma et al, Butterworths Int. Med. Rev.: Clin. Pharmacol. Ther. 35:287 (1984); Israel et al, J. Med. Chem., 16:1 (1973); Morris et al, Polyamines in Biology and Medicine; Dekker, New York, p. 223 (1981) and Wang et al, Biochem. Biophys. Res. Commun., 94:85 (1980).
It is an object of the present invention to provide novel anti-neoplastic, -viral and -retroviral compounds, pharmaceutical compositions and methods of treatment.
The foregoing and other objects are realized by the present invention, one embodiment of which is a pharmaceutical composition comprising an anti-neoplastic, anti-viral, anti-retroviral or anti-psoriasis effective amount of a compound, having one of the formulae: 
Wherein:
R1 and R6 may be the same or different and are H, alkyl or aralkyl having from 1 to 12 carbon atoms,
R2-R5 may be the same or different and are H, R1 or R6;
R7 is H, alkyl, aryl or aralkyl having from 1 to 12 carbon atoms;
m is an integer from 3 to 6, inclusive,
n is an integer from 3 to 6, inclusive; and
a pharmaceutically acceptable carrier therefor.
An additional embodiment of the invention comprises a method of treating a human or non-human animal in need of anti-neoplastic, anti-viral, anti-retroviral or anti-psoriasis therapy comprising administering to the animal an anti-neoplastic, anti-viral, anti-retroviral or anti-psoriasis effective amount of a compound having one of the above formulae.
A further embodiment of the invention comprises a compound having the formula: 
Wherein:
R1-R6 may be the same or different and are methyl, propyl, butyl, pentyl, benzyl or xcex2,xcex2,xcex2-trifluoroethyl;
m is an integer from 3 to 6, inclusive;
n is an integer from 3 to 6, inclusive.
A further embodiment of the invention comprises a compound having the formula:
R1xe2x80x94N1Hxe2x80x94(CH2)3xe2x80x94N2Hxe2x80x94(CH2)3xe2x80x94N3Hxe2x80x94(CH2)4xe2x80x94N4Hxe2x80x94(CH2)3xe2x80x94N5Hxe2x80x94(CH2)3xe2x80x94N6Hxe2x80x94R6xe2x80x83xe2x80x83(II) 
Wherein:
R1 and R6 may be the same or different and are alkyl or aralkyl having from 1 to 12 carbon atoms.
A final embodiment of the invention comprises a compound having the formula: 
Wherein:
R1 and R6 may be the same or different and are alkyl or aralkyl having from 1 to 12 carbon atoms;
R7 is H, alkyl, aralkyl or aryl having from 1 to 12 carbon atoms;
n is an integer from 3 to 6, inclusive.
In compounds of the invention, R1 and R6 are preferably methyl, ethyl, propyl, benzyl, etc., it being understood that the term xe2x80x9caralkylxe2x80x9d is intended to embrace any aromatic group the chemical and physical properties of which do not adversely affect the efficacy and safety of the compound for therapeutic applications. Preferred, however, are the hydrocarbyl aralkyl groups, i.e., comprised only of C and H atoms.
R2-R5 preferably are H, methyl, ethyl, propyl or benzyl.
Compounds of formula (I) are preferably synthesized by first forming a sulfonamide of the polyamine at all of the amino nitrogens (1) to activate the primary amines for monoalkylation, and (2) to protect any secondary nitrogens from alkylation. Suitable sulfonating agents include alkyl, aryl and arylalkyl sulfonating agents of the general structure RSO2X wherein R is alkyl, aryl or arylalkyl and X is a leaving group, e.g., Clxe2x88x92, Brxe2x88x92, etc. The sulfonation is accomplished by reacting the polyamine with 1.0 equivalent of sulfonating agent per nitrogen in the presence of a base, e.g., tertiary amine or a hydroxide. The reaction is best accomplished using aqueous sodium hydroxide as the base and p-toluenesulfonyl chloride (TsCl) a the sulfonating agent in a biphasic solvent systems consisting of an organic solvent, e.g., methylene chloride and water. The sulfonating agent is added in methylene chloride to an aqueous solution of the amine and sodium hydroxide and the reaction proceeds according to the following equation, using spermine as the base compound: 
Where: Ts=p-toluenesulfonyl.
After purification the sulfonamide is next alkylated. The alkylations involve formation of N-anions on the primary amino sulfonamides with a base such as NaH followed by reaction of the N-anion with an alkylating agent RX wherein R is as defined above and X is a leaving group such as Ixe2x88x92, CIxe2x88x92, Brxe2x88x92, p-CH3C6H4SO3xe2x88x92, CH3SO3xe2x88x92.
The alkylation can be carried out in a variety of dipolar aprotic solvents, preferably, N, N-dimethylformamide (DMF). The reaction proceeds according to the following equation: 
After alkylation of the sulfonamide, the sulfonyl protecting groups are next removed under reducing conditions. Although a variety of standard reducing conditions can be utilized (LiAlH4, Li/NH3, catalytic reduction), Na and NH3 function optimally. The reduction proceeds according to the following equation: 
The compounds are isolated as the free amines and then may be converted to and utilized as the corresponding hydrochloride salts by treatment with concentrated HCl. However, they may also be used as salts with any pharmaceutically acceptable acid, e.g., HBr, CH3CO2H, CH3SO3H, etc.
Compounds of formula (II) are preferably prepared by the mono-alkylation of tetratosyl spermine at each of the primary nitrogens by reagents such as N-alkyl-N-(3-chloropropyl)-p-toluenesulfonamide. Terminal alkylation of spermine is carried out using the conditions employed for preparing compound (I) according to the following scheme: 
The alkylating agent is formed by treatment of N-alkyl-p-toluenesulfonamide with excess 1,3 dichloropropane under the aforementioned conditions according to the following scheme: 
After purification of the dialkylated hexatosylated hexaamine, the sulfonyl protecting groups are removed reductively with sodium in liquid ammonia and THF as follows: 
The final product is isolated as the free amine and may be converted to the hydrochloride salt.
Compounds of formula (III) may be prepared by reacting a tetraamine of formula (I) in which R2xe2x80x94R5xe2x95x90H and R1,R6xe2x95x90alkyl or aralkyl with two equivalents of an aldehyde R7CHO, wherein R7xe2x95x90H, alkyl or aralkyl.
Specifically, to N1,N4-diethylspermine tetrahydrochloride is added aqueous NaOH and formalin (two equivalents) to generate the bis-hexahydropyrimidine as follows: 
The invention is illustrated by the following non-limiting examples.